TY  - JOUR
A1  - Gerner, Bettina
A1  - Aghai-Trommeschlaeger, Fatemeh
A1  - Kraus, Sabrina
A1  - Grigoleit, Götz Ulrich
A1  - Zimmermann, Sebastian
A1  - Kurlbaum, Max
A1  - Klinker, Hartwig
A1  - Isberner, Nora
A1  - Scherf-Clavel, Oliver
T1  - A physiologically-based pharmacokinetic model of ruxolitinib and posaconazole to predict CYP3A4-mediated drug–drug interaction frequently observed in graft versus host disease patients
JF  - Pharmaceutics
N2  - Ruxolitinib (RUX) is approved for the treatment of steroid-refractory acute and chronic graft versus host disease (GvHD). It is predominantly metabolized via cytochrome P450 (CYP) 3A4. As patients with GvHD have an increased risk of invasive fungal infections, RUX is frequently combined with posaconazole (POS), a strong CYP3A4 inhibitor. Knowledge of RUX exposure under concomitant POS treatment is scarce and recommendations on dose modifications are inconsistent. A physiologically based pharmacokinetic (PBPK) model was developed to investigate the drug–drug interaction (DDI) between POS and RUX. The predicted RUX exposure was compared to observed concentrations in patients with GvHD in the clinical routine. PBPK models for RUX and POS were independently set up using PK-Sim\(^®\) Version 11. Plasma concentration-time profiles were described successfully and all predicted area under the curve (AUC) values were within 2-fold of the observed values. The increase in RUX exposure was predicted with a DDI ratio of 1.21 (C\(_{max}\)) and 1.59 (AUC). Standard dosing in patients with GvHD led to higher RUX exposure than expected, suggesting further dose reduction if combined with POS. The developed model can serve as a starting point for further simulations of the implemented DDI and can be extended to further perpetrators of CYP-mediated PK-DDIs or disease-specific physiological changes.
KW  - physiologically based pharmacokinetic (PBPK) modeling
KW  - ruxolitinib
KW  - posaconazole
KW  - drug–drug interactions (DDIs)
KW  - graft versus host disease
KW  - cytochrome P450 3A4 (CYP3A4)
KW  - pharmacokinetics
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297261
SN  - 1999-4923
VL  - 14
IS  - 12
ER  - 
TY  - JOUR
A1  - Gerner, Bettina
A1  - Scherf-Clavel, Oliver
T1  - Physiologically based pharmacokinetic modelling of Cabozantinib to simulate enterohepatic recirculation, drug−drug interaction with Rifampin and liver impairment
JF  - Pharmaceutics
N2  - Cabozantinib (CAB) is a receptor tyrosine kinase inhibitor approved for the treatment of several cancer types. Enterohepatic recirculation (EHC) of the substance is assumed but has not been further investigated yet. CAB is mainly metabolized via CYP3A4 and is susceptible for drug–drug interactions (DDI). The goal of this work was to develop a physiologically based pharmacokinetic (PBPK) model to investigate EHC, to simulate DDI with Rifampin and to simulate subjects with hepatic impairment. The model was established using PK-Sim® and six human clinical studies. The inclusion of an EHC process into the model led to the most accurate description of the pharmacokinetic behavior of CAB. The model was able to predict plasma concentrations with low bias and good precision. Ninety-seven percent of all simulated plasma concentrations fell within 2-fold of the corresponding concentration observed. Maximum plasma concentration (C\(_{max}\)) and area under the curve (AUC) were predicted correctly (predicted/observed ratio of 0.9–1.2 for AUC and 0.8–1.1 for C\(_{max}\)). DDI with Rifampin led to a reduction in predicted AUC by 77%. Several physiological parameters were adapted to simulate hepatic impairment correctly. This is the first CAB model used to simulate DDI with Rifampin and hepatic impairment including EHC, which can serve as a starting point for further simulations with regard to special populations.
KW  - physiologically based pharmacokinetic (PBPK) modeling
KW  - Cabozantinib
KW  - enterohepatic recirculation
KW  - drug–drug interactions (DDIs)
KW  - liver impairment
KW  - cytochrome P450 3A4 (CYP3A4)
KW  - pharmacokinetics
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239661
SN  - 1999-4923
VL  - 13
IS  - 6
ER  -